Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters

Hao, Ke; Luk, John M.; Lee, Nikki P.Y.; Mao, Mao; Zhang, Chunsheng; Ferguson, Mark D.; Lamb, John; Dai, Hongyue; Ng, Irene Oi–Lin; Sham, Pak C.; Poon, Ronnie T. P.

doi:10.1186/1471-2407-9-389

Cited by 111 publications

(111 citation statements)

References 24 publications

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“…HCC associates a dismal prognosis because of late presentation of the disease and high risk of postoperative tumour recurrence (Hao et al, 2009). Although the risk factors for HCC are well known (Kemp et al, 2005), the cellular and molecular mechanisms contributing to hepatocarcinogenesis are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

et al. 2012

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Deregulation of Wnt/b-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of b-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/b-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in b-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated b-catenin responsive luciferase activity, and decreased both b-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n ¼ 8), reduction in tumour sizes was observed (P ¼ 0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with b-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of b-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC.

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Section: Introductionmentioning

confidence: 99%

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

et al. 2012

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“…20 The clinical-pathological correlation of HCC patients was analyzed by SPSS for Windows 16.0 (SPSS, Chicago, IL). Categorical data were analyzed via Fisher's exact test, whereas an independent t test was used for continuous data.…”

Section: Patient Samples and Statistical Analysesmentioning

confidence: 99%

Induction of mutant p53‐dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin

Lü

Lee

Kaul

et al. 2011

Intl Journal of Cancer

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Stress protein mortalin (mtHSP70) is highly expressed in cancer cells. It was shown to contribute to carcinogenesis by sequestrating the wild type p53, a key tumor suppressor protein, in the cytoplasm resulting in an abrogation of its transcriptional activation function. We have found that the level of mortalin expression has significant correlation with human hepatocellular carcinoma (HCC) malignancy and therefore investigated whether it interacts with and influences the activities of mutant p53, frequently associated with HCC development. We have detected mortalin-p53 interactions in liver tumor and five HCC cell lines that harbored mutant p53. The data was in contrast to the normal liver and immortalized normal hepatocytes that lacked mortalin-p53 interaction. Furthermore, we have found that the shRNA-mediated mortalin silencing could induce mutant p53-mediated tumor-specific apoptosis in HCC. Such allotment of apoptotic function to mutant p53 by targeting mortalin-p53 interaction in cancer cells is a promising strategy for HCC therapy.Hepatocellular carcinoma (HCC) is a lethal malignancy associated with poor prognosis and the fifth most common cancer worldwide. Effective HCC therapeutics still await molecular understanding of the mechanisms and development of effective reagents that could selectively kill cancer cells. Like any other tumors, HCC has high rate of mutations in tumor suppressor protein p53, and is afflicted in p53-mediated functions including cell cycle arrest and apoptosis.1 Recently, several studies have identified that the mutant p53 executes transcription and nontranscription activities.2,3 Several p53 mutants with a low level of transcriptional activation function were also shown to induce apoptosis in cancer cells demonstrating nontranscriptional apoptotic ability of mutant p53. 4,5 However, in cancer cells such apoptotic function of p53 is often deregulated by multiple pathways including its binding with other proteins.6,7 Restoration of p53-mediated apoptosis is an attractive strategy for cancer therapy.Mortalin/mthsp70/GRP75/PBP74 is a member of the heat shock protein 70 family and has been shown to have multiple functions including chaperoning, mitochondrial import, energy generation and intracellular trafficking. 8,9 It exists in multiple subcellular sites and possesses multiple binding partners. 8,9 Several studies have shown that mortalin is frequently upregulated in cancers and contributes to carcinogenesis. [10][11][12][13][14] It was shown to cause cytoplasmic sequestration of wild type p53 resulting in inhibition of its transcriptional activation and control of centrosome duplication functions, both commonly associated with cancers.15-17 Furthermore, mortalin binding p53 peptides and cationic inhibitor of mortalin (MKT-077) were shown to (i) release p53 from mortalin-p53 complexes, (ii) cause nuclear translocation of p53 and (iii) cause growth arrest of cancer cells that contained wild type p53. 16,18 Mortalin was identified as a marker for HCC metastasis and recurrence by prot...

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“…In China, the mortality rate of HCC is the second highest of all cancers, and the five-year survival rate is less than 5% with nearly 60,000 HCC patients succumbing to the disease every year (2). Increasing evidence suggests that multiple genetic and epigenetic alterations contribute to the tumorigenesis of different cancers.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of PLZF in human hepatocellular carcinoma and its clinical significance

et al. 2014

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Abstract. Promyelocytic leukemia zinc finger (PLZF) acts as a tumor-suppressor gene in a series of cancers including prostate, melanoma, colon cancer and leukemia. However, its role in hepatocellular carcinoma (HCC) has not yet been illustrated. The present study aimed to investigate the expression and epigenetic regulation of PLZF as well as its clinical significance in HCC. We found that the expression of PLZF was significantly downregulated in HCC samples at both the RNA level (P<0.001) and protein level compared with these levels in adjacent normal tissues. The relative expression level of PLZF was also positively correlated with the ALP level (P= 0.026) noted in the HCC patients. However, hypermethylation was only detected in one out of 5 paired HCC samples, indicating that methylation of the selected promoter region (from -1702 to -1388) may not be the major regulatory mechanism for the downregulation of PLZF in HCC. A receiver operating characteristic (ROC) curve was created to evaluate the diagnostic value for differentiating between HCC and benign diseases. The area under the ROC curve (AUC) for indicating the value of PLZF as an HCC biomarker was 0.794 (95% CI, 0.697-0.892; P<0.001). Taken together, our results suggest that PLZF may play an important role in HCC development and may be a potential biomarker for the diagnosis of HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and is the third leading cause of cancer-related death due to its aggressive metastasis and poor clinical diagnosis (1). In China, the mortality rate of HCC is the second highest of all cancers, and the five-year survival rate is less than 5% with nearly 60,000 HCC patients succumbing to the disease every year (2). Increasing evidence suggests that multiple genetic and epigenetic alterations contribute to the tumorigenesis of different cancers. Recently, increased attention has been given to the role of epigenetically regulated genes in HCC.Promyelocytic leukemia zinc finger (PLZF), also known as zinc finger (ZF) and BTB domain containing 16 (ZBTB16), belongs to the POK (POZ and Krüppel ZF) family, which plays an important role in stem cell maintenance and oncogenesis. With DNA binding capability conferred by 9 Krüppel-type zinc-finger motifs at the carboxyl terminus, PLZF can function as a transcriptional factor to regulate various genes (3). In mammals, PLZF is co-expressed with Oct4 in undifferentiated spermatogonia and is essential for stem cell self-renewal (4-6). In acute promyelocytic leukemia, PLZF may function as a chromosomal translocation partner (7). As a transcriptional repressor, PLZF is able to regulate cyclin A2, c-Myc, HoxD11 and other growth-related targets (8).Downregulation of PLZF has been reported in various solid tumors and malignant cell lines. For example, PLZF expression was found to be downregulated in the majority of pancreatic cancer samples among which 35.2% of the samples presented with hypermethylation in the PLZF promoter (9). PLZF was also fou...

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Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters

Cited by 111 publications

References 24 publications

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma

Induction of mutant p53‐dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin

Downregulation of PLZF in human hepatocellular carcinoma and its clinical significance

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